Candida albicans is a ubiquitous fungus which may be found as part of the normal flora of humans. In healthy hosts, serious disease seldom occurs unless some factor alters the balance in favor of the fungus. Unfortunately, precipitating factors such as immunosuppressive therapies and diseases which down-regulate the immune system are becoming more prevalent. Currently, there are no vaccines against human mycoses, and a vaccine capable of stimulating immunity in selected patients prior to immunosuppression would be of considerable value. A novel approach for the development of antifungal vaccines is the use of mucosal immunization. We have recently demonstrated the ability of a novel mucosal adjuvant, developed in our laboratory, to enhance the humoral and cellular immune responses against C. albicans and to induce protection against colonization and lethal i.v. challenge with wild-type C. albicans. Solid protection was achieved following intranasal immunization with heat-killed whole organisms in conjunction with this adjuvant. Both humoral and cellular immune responses against C. albicans were enhanced. A strong DTH response to mannan was observed in animals vaccinated with the killed yeast and adjuvant mixture. Moreover, isotype analysis of anti-Candida antibodies in protected animals revealed a predominance of antibodies of the IgG2a isotype, suggesting a strong Th1 type cytokine response. This proposal seeks to examine the underlying immunological correlates of protection against disseminated candidiasis following mucosal immunization, whether the protection conferred by this vaccine strategy can be passively transferred to naive mice, and whether immunological protection transcends the induction of immunosuppression in experimental animals. Concomitantly, our studies will determine if protection can be achieved in animals that are colonized with Candida prior to vaccination and if cross-protection against other Candida species can be achieved using this mucosal immunization strategy. With the information obtained in the proposed studies, future vaccine strategies can be designed employing similar vaccination protocols for a variety of fungal pathogens. These are important issues because they take us beyond the phenomenological observations of "enhanced immunity" to a more clear understanding of the mechanisms of protection against Candida and the practical implications for the development of antifungal vaccines.